Abstract 2661: Engineered Toxin Bodies (ETBs): Clinical stage immunotoxins with a safer and differentiated profile
Authors: Chris Moore, Lee Robinson, Garrett Cornelison, Joseph Dekker, Roger Waltzman, John Majercak, Joseph Phillips, Jay Zhao, Jason Kim, Eric Poma
Journal: Cancer Research (2023)

Abstract Immunotoxins (the fusion of a bacterial cytotoxic protein with a targeting moiety) have been explored since the 1970s but have been limited in their therapeutic utility because of the propensity to drive a host innate immune response resulting in potentially fatal cytokine elevations and capillary leak syndrome (CLS). Engineered Toxin Bodies (ETBs) represent an important evolution in immunotoxins, overcoming the issues with innate immunity and adding biologic utility not previously seen. ETBs use an antibody-based targeting domain genetically fused to a de-immunized form of the Shiga-like toxin A subunit (SLTA). Like previous immunotoxins, ETBs bind and induce cell-death in a target-specific manner but have additional biology not inherent to other immunotoxins. ETBs can induce their own internalization, allowing for the targeting of poorly/non internalizing receptors. ETBs can deliver other payloads like viral class I antigen or small molecules in addition to SLTA, allowing for multiple MOAs. And, most importantly, we have de-immunized SLTA through genetic engineering to create ETBs devoid of innate immune effects/CLS seen with previous immunotoxins. Three ETBs (MT-0169, MT-5111, and MT-6402) are currently in clinical studies across different targets (CD38, HER2, PD-L1) and across hematologic malignancies, solid tumor, and immuno-oncology indications. To date, no clinical manifestations of CLS have been observed in 80+ patients; in contrast, the rate of CLS for approved immunotoxins ranges for 33% to &amp;gt;50%. In general, all three ETBs have shown good tolerability with little off-target toxicity and all three ETBs have shown monotherapy clinical benefit in heavily pre-treated patients. MT-6402, an ETB targeting PD-L1, is the first ETB to carry the additional mechanism of antigen seeding. Along with its ability to destroy ribosome in a PD-L1-targeted fashion, MT-6402 can deliver a class I antigen derived from human cytomegalovirus (CMV) to the ER, allowing for presentation of the antigen in complex with MHC class I on the cell surface of a tumor cell. Early clinical data demonstrate antigen seeding with MT-6402 can result in T-cells specific to the seeded CMV antigen mounting an immune response to the tumor. ETBs represent a unique and wholly distinct scaffold for drug development in oncology. ETBs allow for the targeting of non-internalizing receptors that are not amenable to ADCs. ETBs have a mechanism of cell-kill (enzymatic and irreversible ribosomal destruction) that is distinct from any approved agent in oncology. ETBs can also deliver additional payloads to drive unique biology like the alteration of tumor immunophenotype. Here we describe three active clinical stage programs with encouraging safety and efficacy data that represent a transformation of the immunotoxin landscape into a more viable therapeutic approach to target validated as well as typically intractable clinical cancer targets. Citation Format: Chris Moore, Lee Robinson, Garrett Cornelison, Joseph Dekker, Roger Waltzman, John Majercak, Joseph Phillips, Jay Zhao, Jason Kim, Eric Poma. Engineered Toxin Bodies (ETBs): Clinical stage immunotoxins with a safer and differentiated profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2661.